Compositions and methods for the treatment of fungal infections

ABSTRACT

The invention relates to the compounds or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or Formula X and, the methods for the treatment of fungal infections may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fungal infections.

PRIORITY

The present application claims the benefit of Indian Provisional PatentApplication No. 201641040639 filed on 28 Nov. 2016, and IndianProvisional Patent Application No. 201741012687 filed on 7 Apr. 2017,the entire disclosure of which is relied on for all purposes and isincorporated into this application by reference.

FIELD OF THE INVENTION

This disclosure generally relates to compounds and compositions for thetreatment of fungal infections. More particularly, this inventionrelates to treating subjects with a pharmaceutically acceptable dose ofcompounds, crystals, solvates, enantiomer, stereoisomer, esters,hydrates, or mixtures thereof.

BACKGROUND OF THE INVENTION

Invasive infection due to Candida species is largely a conditionassociated with medical progress, and is widely recognized as a majorcause of morbidity and mortality in the healthcare environment. Thereare at least 15 distinct Candida species that cause human disease,but >90% of invasive disease is caused by the 5 most common pathogens,C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei.Each of these organisms has unique virulence potential, antifungalsusceptibility, and epidemiology, but taken as a whole, significantinfections due to these organisms are generally referred to as invasivecandidiasis.

Oropharyngeal candidiasis is the current term used to describe diseaseof the linings of the oral cavity caused almost always by Candidaalbicans. Disease caused by Candida species, including oropharyngealcandidiasis, encompasses a broad spectrum, from the trivial to the mostlife-threatening of infections. Because the fungus is believed to residein low numbers on mucous membranes in the healthy host, disease isattributable to a reduction in host defenses, and the host responsedepends in great measure on where lesions arise. For example, in themost common presentation of oropharyngeal candidiasis, pseudomembranouscandidiasis, Gram staining of the curd-like lesions on buccal membranesdemonstrates a tangle of oral bacteria, proliferating fungus(predominately blastoconidia and pseudohyphae), and polymorphonuclearleukocytes in an eosinophilic background.

Other forms of oropharyngeal candidiasis manifest as glossitis orerythema in the fissures of the mouth or beneath denture plates.Furthermore, changes in environmental factors can prompt the developmentof adaptive responses in individual microorganisms to new environmentalconditions and introduce more pathogenic microorganisms into themicrobial community. Non-mutans streptococci and Actinomyces arepredominant in the supragingival ecosystem that cause acidification,resulting in both demineralization of tooth surface and introduction ofmore cariogenic microorganisms, mutans streptococci, to the ecosystem.

Fusobacteria and Prevotella neutralize subgingival environment pH bynitrogenous metabolism and stimulate GCF efflux. The neutral pH andnitrogenous environment increases the proteolytic activity of Prevotellaand facilitates the establishment of a more acid-intolerant, butperiodontopathogenic bacterium, Porphyromonas gingivalis.

Managing acute pathology of often relies on the addressing underlyingpathology and symptoms of the disease. There is currently a need in theart for new compositions to treatment or delay of the onset of fungalinfections and its associated complications progression.

SUMMARY OF THE INVENTION

The present invention provides compounds, compositions containing thesecompounds and methods for using the same to treat, prevent and/orameliorate the effects of the conditions such as fungal infections.

The invention herein provides compositions comprising of formula I orpharmaceutical acceptable hydrates or solvates thereof. The inventionalso provides pharmaceutical compositions comprising one or morecompounds of formula I or intermediates thereof and one or more ofpharmaceutically acceptable carriers, vehicles or diluents. Thesecompositions may be used in the treatment of fungal infections and itsassociated complications.

and pharmaceutically acceptable hydrates, solvates, enantiomers, andstereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid, arachidonic acidor

wherein, within the provisoeach R₁, R₂ and R₃ independently represents

In another aspect, the compounds of formula II are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In certain embodiments, the compounds of formula III are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In an additional aspect, the compounds of formula IV are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid, arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In an additional aspect, the compounds of formula V are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In an additional aspect, the compounds of formula VI are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In an additional aspect, the compounds of formula VII are described:

R₁ is selected from OD, OCH₃, OCOCH₃, NULL,

R₂ is

wherein,each R₃ and R₄ independently represents

In another aspect, the compounds of formula VIII are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In another aspect, the compounds of formula IX are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

In another aspect, the compounds of formula X are described:

and pharmaceutically acceptable hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein,

RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleicacid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid,thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fattyacids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methylfuroate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid,capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidicacid and arachidonic acidor

wherein,each R₁, R₂ and R₃ independently represents

Herein the application also provides a kit comprising any of thepharmaceutical compositions disclosed herein. The kit may compriseinstructions for use in the treatment of fungal infections or itsrelated complications.

The application also discloses a pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compositions herein.In some aspects, the pharmaceutical composition is formulated for oralsolution, oral rinsing solution, oral antiseptic solution, systemicadministration, oral administration, sustained release, parenteraladministration, injection, subdermal administration, or transdermaladministration.

Herein, the application additionally provides kits comprising thepharmaceutical compositions described herein. The kits may furthercomprise instructions for use in the treatment of fungal infections orits related complications.

The compositions described herein have several uses. The presentapplication provides, for example, methods of treating a patientsuffering from fungal infections or its related complications manifestedfrom metabolic or genetic conditions or disorders, metabolic diseases,chronic diseases or disorders; neurodegenerative disorders, metaboliccondition, Hepatology, Cancer, Respiratory, Hematological, Orthopedic,Cardiovascular, Renal, Skin, Vascular or Ocular complications.

In the illustrative embodiments, examples of compounds of formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX and Formula X are as set forth below:

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, lngold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic condition” refers to an Inbornerrors of metabolism (or genetic metabolic conditions) are geneticdisorders that result from a defect in one or more metabolic pathways;specifically, the function of an enzyme is affected and is eitherdeficient or completely absent.

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include withoutlimitation intravenous, intramuscular, intrapleural, intravascular,intrapericardial, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probabilityrelated diseases patient will suffer from abnormalities or complicationand/or terminal platelet aggregation or failure and/or death (i.e.mortality) within a defined time window (predictive window) in thefuture. The mortality may be caused by the central nervous system orcomplication. The predictive window is an interval in which the subjectwill develop one or more of the said complications according to thepredicted probability. The predictive window may be the entire remaininglifespan of the subject upon analysis by the method of the presentinvention.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating fungal infections, oral candidiasis, fungal infections,viral infections, bacterial infections, and other microbial relateddiseases or any other medical condition, is well understood in the art,and includes administration of a composition which reduces the frequencyof, or delays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a solvate orhydrate or composition disclosed herein that produces some desiredeffect at a reasonable benefit/risk ratio applicable to any medicaltreatment. In certain embodiments, the term refers to that amountnecessary or sufficient to eliminate or reduce medical symptoms for aperiod of time. The effective amount may vary depending on such factorsas the disease or condition being treated, the particular targetedconstructs being administered, the size of the subject, or the severityof the disease or condition. One of ordinary skill in the art mayempirically determine the effective amount of a particular compositionwithout necessitating undue experimentation.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the hydrates or solvates and compositions from the subjectcompositions. It is to be noted that dosage values may also vary withthe severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions. Typically, dosing will be determinedusing techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular solvate or hydrate or composition may be adjusted toaccommodate variations in the treatment parameters. Such treatmentparameters include the clinical use to which the preparation is put,e.g., the site treated, the type of patient, e.g., human or non-human,adult or child, and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (e.g., through hydrolysis) with concomitant release of anymaterial incorporated therein, e.g., an therapeutic and/or biologicallyactive solvate or hydrate and/or composition, for a sustained orextended period (as compared to the release from a bolus). This releasemay result in prolonged delivery of therapeutically effective amounts ofany of the therapeutic agents disclosed herein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a solvate orhydrate or composition disclosed herein that produces some desiredeffect at a reasonable benefit/risk ratio applicable to any medicaltreatment. In certain embodiments, the term refers to that amountnecessary or sufficient to eliminate or reduce medical symptoms for aperiod of time. The effective amount may vary depending on such factorsas the disease or condition being treated, the particular targetedconstructs being administered, the size of the subject, or the severityof the disease or condition. One of ordinary skill in the art mayempirically determine the effective amount of a particular compositionwithout necessitating undue experimentation.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable hydrates orsolvates of said prodrugs.

This application also discloses a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the composition of a compoundof formula I, formula II, formula III, formula IV, formula V, formulaVI, formula VII, formula VIII, formula IX or Formula X may be formulatedfor systemic or topical or oral administration. The pharmaceuticalcomposition may be also formulated for oral administration, oralsolution, injection, subdermal administration, or transdermaladministration. The pharmaceutical composition may further comprise atleast one of a pharmaceutically acceptable stabilizer, diluent,surfactant, filler, binder, and lubricant.

In many embodiments, the pharmaceutical compositions described hereinwill incorporate the disclosed compounds and compositions (formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX, formula X to be delivered in an amountsufficient to deliver to a patient a therapeutically effective amount ofa compound of formula I, formula II, formula III, formula IV, formula V,formula VI, formula VII, formula VIII, formula IX or Formula X orcomposition as part of a prophylactic or therapeutic treatment. Thedesired concentration of formula I, formula II, formula III, formula IV,formula V, formula VI, formula VII, formula VIII, formula IX or FormulaX or its pharmaceutical acceptable hydrates or solvates will depend onabsorption, inactivation, and excretion rates of the drug as well as thedelivery rate of the hydrates or solvates and compositions from thesubject compositions. It is to be noted that dosage values may also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions. Typically, dosing will be determinedusing techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of formula I, formula II, formula III, formulaIV, formula V, formula VI, formula VII, formula VIII, formula IX orFormula X may be adjusted to accommodate variations in the treatmentparameters. Such treatment parameters include the clinical use to whichthe preparation is put, e.g., the site treated, the type of patient,e.g., human or non-human, adult or child, and the nature of the diseaseor condition.

The concentration and/or amount of any compound of formula I, formulaII, formula III, formula IV, formula V, formula VI, formula VII, formulaVIII, formula IX or Formula X may be readily identified by routinescreening in animals, e.g., rats, by screening a range of concentrationand/or amounts of the material in question using appropriate assays.Known methods are also available to assay local tissue concentrations,diffusion rates of the hydrates or solvates or compositions, and localblood flow before and after administration of therapeutic formulationsdisclosed herein. One such method is microdialysis, as reviewed by T. E.Robinson et al., 1991, microdialysis in the neurosciences, Techniques,volume 7, Chapter 1. The methods reviewed by Robinson may be applied, inbrief, as follows. A microdialysis loop is placed in situ in a testanimal. Dialysis fluid is pumped through the loop. When compounds withformula I, formula II, formula III, formula IV, formula V, formula VI,formula VII, formula VIII, formula IX or Formula X such as thosedisclosed herein are injected adjacent to the loop, released drugs arecollected in the dialysate in proportion to their local tissueconcentrations. The progress of diffusion of the hydrates or solvates orcompositions may be determined thereby with suitable calibrationprocedures using known concentrations of hydrates or solvates orcompositions.

In certain embodiments, the dosage of the subject compounds of formulaI, formula II, formula III, formula IV, formula V, formula VI, formulaVII, formula VIII, formula IX or Formula X provided herein may bedetermined by reference to the plasma concentrations of the therapeuticcomposition or other encapsulated materials. For example, the maximumplasma concentration (Cmax) and the area under the plasmaconcentration-time curve from time 0 to infinity may be used.

Generally, in carrying out the methods detailed in this application, aneffective dosage for the compounds of formula I, formula II, formulaIII, formula IV, formula V, formula VI, formula VII, formula VIII,formula IX or Formula X is in the range of about 0.01 mg/kg/day to about100 mg/kg/day in single or divided doses, for instance 0.01 mg/kg/day toabout 50 mg/kg/day in single or divided doses. The compounds of FormulasI may be administered at a dose of, for example, less than 0.2mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX or Formula X may also be administered to ahuman patient at a dose of, for example, between 0.1 mg and 1000 mg,between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0,100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certainembodiments, the compositions herein are administered at an amount thatis less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of thecompound of formula I, formula II, formula III, formula IV, formula V,formula VI, formula VII, formula VIII, formula IX or Formula X requiredfor the same therapeutic benefit.

An effective amount of the compounds of formula I, formula II, formulaIII, formula IV, formula V, formula VI, formula VII, formula VIII,formula IX or Formula X described herein refers to the amount of one ofsaid hydrates or solvates or compositions which is capable of inhibitingor preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate,ameliorate, halt, restrain, slow or reverse the progression, or reducethe severity of a complication resulting from nerve damage ordemyelization and/or elevated reactive oxidative-nitrosative speciesand/or abnormalities in neurotransmitter homeostasis's, in patients whoare at risk for such complications. As such, these methods include bothmedical therapeutic (acute) and/or prophylactic (prevention)administration as appropriate. The amount and timing of compositionsadministered will, of course, be dependent on the subject being treated,on the severity of the affliction, on the manner of administration andon the judgment of the prescribing physician. Thus, because ofpatient-to-patient variability, the dosages given above are a guidelineand the physician may titrate doses of the drug to achieve the treatmentthat the physician considers appropriate for the patient. In consideringthe degree of treatment desired, the physician must balance a variety offactors such as age of the patient, presence of preexisting disease, aswell as presence of other diseases.

The compositions provided by this application may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents, in eithersingle or multiple doses. Suitable pharmaceutical carriers, vehicles anddiluents include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the compositions and the pharmaceutically acceptablecarriers, vehicles or diluents are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such asL-arginine, sodium citrate, calcium carbonate and calcium phosphate maybe employed along with various disintegrates such as starch, alginicacid and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof. Thecompounds of formula I, formula II, formula III, formula IV, formula V,formula VI, formula VII, formula VIII, formula IX or formula X may alsocomprise enterically coated comprising of various excipients, as is wellknown in the pharmaceutical art.

For parenteral administration, solutions of the compositions may beprepared in (for example) sesame or peanut oil, aqueous propyleneglycol, or in sterile aqueous solutions may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of formula I, formula II, formula III, formulaIV, formula V, formula VI, formula VII, formula VIII, formula IX orFormula X disclosed herein, for instance, compounds of formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX or Formula X or pharmaceutical acceptablehydrates or solvates of a compounds of formula I, formula II, formulaIII, formula IV, formula V, formula VI, formula VII, formula VIII,formula IX or Formula X.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of theneurological disease; the type of host involved, including its age,health and weight; the kind of concurrent treatment, if any; thefrequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredientsare: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 toabout 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host bodyweight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions ofsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL™ Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants,antioxidants, and mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their hydrates or solvates, such as magnesium stearate andstearic acid, talc, glycerides waxes, and mixtures thereof. Suitableglidants include, but are not limited to, colloidal silicon dioxide.Suitable release-modifying excipients include, but are not limited to,insoluble edible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof, and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirhydrates or solvates, and mixtures thereof. Examples of suitable fattyacid esters include, but are not limited to, sucrose fatty acid esters,mono-, di-, and triglycerides, glyceryl behenate, glycerylpalmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryltrilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof.Examples of suitable phospholipids include phosphotidyl choline,phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, andmixtures thereof. Examples of suitable waxes include, but are notlimited to, carnauba wax, spermaceti wax, beeswax, candelilla wax,shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate, and mixtures thereof. Examples of superdisintegrants include, but are not limited to, croscarmellose sodium,sodium starch glycolate and cross-linked povidone (crospovidone). In oneembodiment the tablet core contains up to about 5 percent by weight ofsuch super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate hydrates or solvates, andmixtures thereof. Examples of preservatives include, but are not limitedto, citric acid, tartaric acid, lactic acid, malic acid, acetic acid,benzoic acid, and sorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an averagethickness of at least 50 microns, such as from about 50 microns to about2500 microns; e.g., from about 250 microns to about 1000 microns. Inembodiment, the immediate release coating is typically compressed at adensity of more than about 0.9 g/cc, as measured by the weight andvolume of that specific layer.

In one embodiment, the immediate release coating contains a firstportion and a second portion, wherein at least one of the portionscontains the second pharmaceutically active agent. In one embodiment,the portions contact each other at a center axis of the tablet. In oneembodiment, the first portion includes the first pharmaceutically activeagent and the second portion includes the second pharmaceutically activeagent.

In one embodiment, the first portion contains the first pharmaceuticallyactive agent and the second portion contains the second pharmaceuticallyactive agent. In one embodiment, one of the portions contains a thirdpharmaceutically active agent. In one embodiment one of the portionscontains a second immediate release portion of the same pharmaceuticallyactive agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blendof materials prior to addition to the coated tablet core. In anotherembodiment the outer coating portion is included of a dried granulationincluding the pharmaceutically active agent.

Formulations with different drug release mechanisms described abovecould be combined in a final dosage form containing single or multipleunits. Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, or granules in a solid or liquid form.Typical, immediate release formulations include compressed tablets,gels, films, coatings, liquids and particles that can be encapsulated,for example, in a gelatin capsule. Many methods for preparing coatings,covering or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, aplurality of drug-containing beads, granules or particles, or an outerlayer of a coated core dosage form, contains a therapeutically effectivequantity of the active agent with conventional pharmaceuticalexcipients. The immediate release dosage unit may or may not be coated,and may or may not be admixed with the delayed release dosage unit orunits (as in an encapsulated mixture of immediate releasedrug-containing granules, particles or beads and delayed releasedrug-containing granules or beads).

Extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The Science andPractice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000). A diffusion system typically consists of one oftwo types of devices, reservoir and matrix, which are wellknown anddescribed in die art. The matrix devices are generally prepared bycompressing the drug with a slowly dissolving polymer carrier into atablet form.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core; using coating or compression processes or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Delayed release dosage formulations are created by coating a soliddosage form with a film of a polymer which is insoluble in the acidenvironment of the stomach, but soluble in the neutral environment ofsmall intestines. The delayed release dosage units can be prepared, forexample, by coating a drug or a drug-containing composition with aselected coating material. The drug-containing composition may be atablet for incorporation into a capsule, a tablet for use as an innercore in a “coated core” dosage form, or a plurality of drug-containingbeads, particles or granules, for incorporation into either a tablet orcapsule.

A pulsed release dosage form is one that mimics a multiple dosingprofile without repeated dosing and typically allows at least a twofoldreduction in dosing frequency as compared to the drug presented as aconventional dosage form (e.g., as a solution or prompt drug-releasing,conventional solid dosage form). A pulsed release profile ischaracterized by a time period of no release (lag time) or reducedrelease followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of activeagent. In one embodiment of dosage forms that mimic a twice daily dosingprofile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60wt. %, of the total amount of active agent in the dosage form isreleased in the initial pulse, and, correspondingly approximately 70 wt.% to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount ofactive agent in the dosage form is released in the second pulse. Fordosage forms mimicking the twice daily dosing profile, the second pulseis preferably released approximately 3 hours to less than 14 hours, andmore preferably approximately 5 hours to 12 hours, followingadministration.

Another dosage form contains a compressed tablet or a capsule having adrug-containing immediate release dosage unit, a delayed release dosageunit and an optional second delayed release dosage unit. In this dosageform, the immediate release dosage unit contains a plurality of beads,granules particles that release drug substantially immediately followingoral administration to provide an initial dose. The delayed releasedosage unit contains a plurality of coated beads or granules, whichrelease drug approximately 3 hours to 14 hours following oraladministration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, may be prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of one or more compounds of formula I, formula II, formula III,formula IV, formula V, formula VI, formula VII, formula VIII, formulaIX, formula X, or other active agents are known, or will be apparent inlight of this disclosure, to those skilled in this art. For examples ofmethods of preparing pharmaceutical compositions, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19thEdition (1995).

In addition, in certain embodiments, subject compositions of the presentapplication maybe lyophilized or subjected to another appropriate dryingtechnique such as spray drying. The subject compositions may beadministered once, or may be divided into a number of smaller doses tobe administered at varying intervals of time, depending in part on therelease rate of the compositions and the desired dosage.

Formulations useful in the methods provided herein include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal, aerosol and/or parenteral administration. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. The amountof a subject composition which may be combined with a carrier materialto produce a single dose may vary depending upon the subject beingtreated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the stepof bringing into association subject compositions with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a subject composition with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

The compounds of formula I, formula II, formula III, formula IV, formulaV, formula VI, formula VII, formula VIII, formula IX or Formula Xdescribed herein may be administered in inhalant or aerosolformulations. The inhalant or aerosol formulations may comprise one ormore agents, such as adjuvants, diagnostic agents, imaging agents, ortherapeutic agents useful in inhalation therapy. The final aerosolformulation may for example contain 0.005-90% w/w, for instance0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to thetotal weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers and/or anyof the following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using lactose or milk sugars, as wellas high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the subject compositions, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax, or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the appropriate body cavity and release theencapsulated compound(s) and composition(s). Formulations which aresuitable for vaginal administration also include pessaries, tampons,creams, gels, pastes, foams, or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. A subject composition may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. For transdermaladministration, the complexes may include lipophilic and hydrophilicgroups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition tosubject compositions, other carriers, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Powders and sprays may contain, in additionto a subject composition, excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of such substances. Sprays may additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

In another embodiment, a transdermal patch may comprise: a substratesheet comprising a composite film formed of a resin compositioncomprising 100 parts by weight of a polyvinyl chloride-polyurethanecomposite and 2-10 parts by weight of astyrene-ethylene-butylene-styrene copolymer, a first adhesive layer onthe one side of the composite film, and a polyalkylene terephthalatefilm adhered to the one side of the composite film by means of the firstadhesive layer, a primer layer which comprises a saturated polyesterresin and is formed on the surface of the polyalkylene terephthalatefilm; and a second adhesive layer comprising a styrene-diene-styreneblock copolymer containing a pharmaceutical agent layered on the primerlayer.

Transdermal patches may be passive or active. Passive transdermal drugdelivery systems currently available, such as the nicotine, estrogen andnitroglycerine patches, deliver small-molecule drugs. Many of the newlydeveloped proteins and peptide drugs are too large to be deliveredthrough passive transdermal patches and may be delivered usingtechnology such as electrical assist (iontophoresis) for large-moleculedrugs.

Iontophoresis is a technique employed for enhancing the flux of ionizedsubstances through membranes by application of electric current. Oneexample of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646to Theeuwes. The principal mechanisms by which iontophoresis enhancesmolecular transport across the skin are (a) repelling a charged ion froman electrode of the same charge, (b) electroosmosis, the convectivemovement of solvent that occurs through a charged pore in response thepreferential passage of counter-ions when an electric field is appliedor (c) increase skin permeability due to application of electricalcurrent.

Methods and compositions for the treatment of oral infectious diseases.Among other things, herein is provided a method of treating oralinfectious diseases, comprising administering to a patient in needthereof a therapeutically effective amount of compound of Formula's inthe specification as a general scheme for acid part [6] & [6A] synthesisand formula I, formula II, formula III, formula IV, formula V, formulaVI, formula VII, formula VIII, formula IX or Formula X:

General Scheme for Acid Part (6) Synthesis

Synthesis of 2-oxopropane-1,3-diyl dioctanoate (3)

To an ice cold solution of 1,3-dihydroxypropan-2-one (1, 25.0 g, 0.277mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine(10.17 g, 0.083 mol) and pyridine (49.2 mL, 0.610 mol) and stirred fornext 5 min. To the above mixture octanoyl chloride (2, 105.4 mL, 0.610mol) was added dropwise at 0° C. and the reaction mixture was stirred atroom temperature for 16 h. After completion, reaction mixture wasfiltered; the solid was washed with dichloromethane (100 mL), filtratewas washed with brine (200 mL), saturated solution of sodium bicarbonate(200 mL) and 0.1 N HCl solution (100 mL). Organic layer was separatedand dried over anhydrous sodium sulfate and solvent was removed underreduced pressure to get crude. The crude was purified by silica gel(100-200 mesh) column chromatography eluting with 10% ethyl acetate inhexanes to afford the desired product as white solid. Yield: 70.0 g,73%.

MS (ESI) m/z 343.19[M+1]±;

¹H NMR (400 MHz, DMSO-d6); δ 4.84 (s, 4H), 2.37 (t, J=7.2 Hz, 4H),1.45-1.62 (m, 4H), 1.15-1.35 (m, 16H), 0.78-0.92 (m, 6H).

Synthesis of 2-hydroxypropane-1,3-diyl dioctanoate (4)

To an ice cold solution of 2-oxopropane-1,3-diyl dioctanoate (3, 70.0 g,0.204 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL)followed by the portion wise addition of sodium cyanoborohydride (15.43g, 0.245 mol). The reaction mixture was stirred at room temperature for16 h. After completion, reaction mixture was diluted with water (400 mL)and extracted with ethyl acetate (3×200 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and solvent was removedunder reduced pressure. The crude thus obtained was purified by silicagel (100-200 mesh) column chromatography eluting with 12 to 15% ethylacetate in hexanes to afford the desired product 4 as yellow liquid.Yield: 50.0 g, 71%.

MS (ESI) m/z 345.29[M+1]⁺;

¹H NMR (400 MHz, DMSO-d6): δ 5.25 (d, J=5.2 Hz, 1H), 3.92-4.03 (m, 4H),3.81-3.90 (m, 1H), 2.29 (t, J=7.6 Hz, 4H), 1.45-1.59 (m, 4H), 1.12-1.35(m, 16H), 0.85 (t, J=6.8 Hz, 6H).

Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid(6)

To a solution of 2-hydroxypropane-1,3-diyl dioctanoate (4, 50.0 g, 0.145mol) in chloroform (200 mL), dihydrofuran-2,5-dione (5, 17.44 g, 0.174mol) and triethylamine (30.0 mL, 0.218 mol) were added at roomtemperature. The reaction mixture was stirred at 120° C. for 3 h. Aftercompletion, reaction mixture was diluted with water (200 mL) andextracted with 1,2 dichloromethane (3×200 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude thus obtained was purified by silica gel(100-200 mesh) column chromatography eluting with 10 to 15% ethylacetate in hexanes to affored the desired product 6 as white solid.Yield: 47.0 g, 72%.

MS (ESI) m/z 443.2[M−1];

¹H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 5.12-5.22 (m, 1H), 4.18-4.25(m, 2H), 4.09-4.17 (m, 2H), 2.42-2.50 (m, 4H), 2.29 (t, J=7.24 Hz, 4H),1.44-1.55 (m, 4H), 1.15-1.31 (m, 16H), 0.79-0.90 (m, 6H).

General Scheme for Acid Part (6A) Synthesis

Synthesis of 2-oxopropane-1,3-diyl didodecanoate (3A)

To an ice cold solution of 1,3-dihydroxypropan-2-one (1, 30.0 g, 0.33mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine(20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred fornext 5 min. To the above mixture dodecanoyl chloride 2A (218.50 g, 1.167mol) was added dropwise at 0° C. and the reaction mixture was stirred atroom temperature for 16 h. After completion, reaction mixture wasfiltered; the solid was washed with dichloromethane (100 mL), filtratewas washed with brine (200 mL), saturated solution of sodium bicarbonate(200 mL) and 0.1 N HCl solution (100 mL). Organic layer was separatedand dried over anhydrous sodium sulfate and solvent was removed underreduced pressure to get crude. The crude was triturated with diethylether to afford the desired product 3A as white solid. Yield: 78 g, 51%.MS (ESI) m/z 455.37 [M+1]⁺;

¹H NMR (400 MHz, DMSO-d6); δ 4.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H),1.55-1.25 (m, 32H), 0.87 (m, 6H).

Synthesis of 2-hydroxypropane-1,3-diyl didodecanoate (4A)

To an ice cold solution of 2-oxopropane-1,3-diyl didodecanoate 3A (75.0g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL)followed by the portion wise addition of sodium cyanoborohydride (12.41g, 0.198 mol). The reaction mixture was stirred at room temperature for16 h. After completion, reaction mixture was diluted with water (400 mL)and extracted with ethyl acetate (3×200 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and solvent was removedunder reduced pressure. The crude was triturated with diethyl ether toafford the desired product 4A as white solid. Yield: 60.0 g, 80%.

MS (ESI) m/z 457.48[M+1]⁺;

¹H NMR (400 MHz, DMSO-d6); δ 5.26 (d, J=5.2 Hz, 1H), 3.92-3.98 (m, 4H),2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H), 0.83 (m, 6H).

Synthesis of 4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoicacid (6A)

To a solution of 2-hydroxypropane-1,3-diyl didodecanoate 4A (40.0 g,0.087 mol) in chloroform (200 mL), dihydrofuran-2,5-dione 5 (10.50 g,0.105 mol) and triethylamine (18.50 mL, 0.131 mol) were added at roomtemperature. The reaction mixture was stirred at 120° C. for 3 h. Aftercompletion, reaction mixture was diluted with water (200 mL) andextracted with 1,2 dichloromethane (3×200 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude thus obtained was purified by silica gel(100-200 mesh) column chromatography eluting with 25 to 30% ethylacetate in hexanes to afford the desired product 6A as white solid.Yield: 20.0 g, 41%.

MS (ESI) m/z 555.40[M−1];

¹H NMR (400 MHz, DMSO-d6); δ 12.30 (s, 1H), 5.17 (m, 1H), 4.18-4.25 (m,4H), 2.50-2.47 (m, 8H), 1.23-1.25 (m, 36H), 0.83 (m, 6H).

Synthesis of4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoate1-(2-((2,4-dichlorobenzyl)oxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imidazol-1-ium(8)

To a solution of4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid 6A (6.0 g,0.013 mol) in acetonitrile (150 mL) was added1-(2-((2,4-dichlorobenzyl)oxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imidazole7 (5.62 g, 0.013 mol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 6 h followed by the evaporationof solvent under reduced pressure to get the desired product 8 ascolorless viscous oil. Yield: 11.62 g, quant.

Synthesis of 4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoate1-((2-chlorophenyl) diphenylmethyl)-1H-imidazol-3-ium 10

To a solution of4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid 6A (7.0 g,0.016 mol) in acetonitrile (150 mL) was added1-((2-chlorophenyl)diphenylmethyl)-1H-imidazole 9 (5.52 g, 0.016 mol) atambient temperature. The resulting reaction mixture was heated up to 50°C. for next 6 h followed by the evaporation of solvent under reducedpressure to get the desired product 10 as white semi solid. Yield: 12.52g, quant.

Synthesis of 4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoate1-((4-((4-(4-(4-(1-(sec-butyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-yl)phenoxy)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazol-1-ium12

To a solution of4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid 6A (6.0 g,0.013 mol) in acetonitrile (150 mL) was added4-(4-(4-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one11 (9.17 g, 0.013 mol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 6 h followed by the evaporationof solvent under reduced pressure to get the desired product 12 asoff-white solid. Yield: 15.17 g, quantitative.

Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoate4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)-1-(4-(1-((25,35)-2-hydroxypentan-3-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-ium14 [Formula I]

To a solution of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoicacid 6 (4.20 g, 0.009 mol) in acetonitrile (100 mL) was added4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one13 (6.63 g, 0.009 mol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 6 h followed by the evaporationof solvent under reduced pressure to get the desired product 14, FORMULAI as off-white hygroscopic solid. Yield: 10.83 g, quant.

Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoate4-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-5-fluoropyrimidin-1-ium16 [FORMULA II]

To a solution of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoicacid 6 (6.0 g, 0.013 mol) in acetonitrile (150 mL) was added(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol15 (4.72 g, 0.013 mol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 6 h followed by the evaporationof solvent under reduced pressure to get the desired product 16, FORMULAII as off-white semi solid. Yield: 10.72 g, quantitative.

Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoateN,6,6-trimethyl-N-(naphthalen-1-ylmethyl)hept-2-en-4-yn-1-aminium 18

To a solution of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoicacid 6 (6.50 g, 0.014 mol) in acetonitrile (150 mL) was addedN,6,6-trimethyl-N-(naphthalen-1-ylmethyl)hept-2-en-4-yn-1-amine 17 (4.20g, 0.014 mol) at ambient temperature. The resulting reaction mixture washeated up to 50° C. for next 6 h followed by the evaporation of solventunder reduced pressure to get the desired product 18, FORMULA III ascolorless liquid. Yield: 10.70 g, quantitative.

Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoateN-(4-(tert-butyl)benzyl)-N-methyl-1-(naphthalen-1-yl)methanaminium 20

To a solution of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoicacid 6 (6.0 g, 0.013 mol) in acetonitrile (150 mL) was addedN-(4-(tert-butyl)benzyl)-N-methyl-1-(naphthalen-1-yl)methanamine 19(4.29 g, 0.013 mol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 6 h followed by the evaporationof solvent under reduced pressure to get the desired product 20, FORMULAIV as colorless liquid. Yield: 10.29 g, quantitative.

Synthesis of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoate5-fluoro-2-oxo-2,3-dihydropyrimidin-4-aminium 22

To a solution of 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoicacid 6 (8.0 g, 0.018 mol) in acetonitrile (150 mL) was6-amino-5-fluoropyrimidin-2(1H)-one 17 (2.52 g, 0.018 mol) at ambienttemperature. The resulting reaction mixture was heated up to 50° C. fornext 6 h followed by the evaporation of solvent under reduced pressureto get the desired product 22, FORMULA V as off-white semi solid(hygroscopic). Yield: 10.52 g, quantitative.

Synthesis of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid

Synthesis of 2-oxopropane-1,3-diyl didodecanoate (3)

To an ice cold solution of 1,3-dihydroxypropan-2-one (1, 30.0 g, 0.33mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine(20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred fornext 5 min. To the above reaction mixture dodecanoyl chloride 2 (218.50g, 1.167 mol) was added dropwise at 0° C. and the reaction mixture wasstirred at room temperature for 16 h. After completion, reaction mixturewas filtered, the solid was washed with dichloromethane (100 mL),filtrate was washed with brine (200 mL), saturated solution of sodiumbicarbonate (200 mL) and 0.1 N HCl solution (100 mL). The organic layerwas separated, dried over anhydrous sodium sulfate and solvent wasremoved under reduced pressure to get crude. The crude was trituratedwith diethyl ether to afford the desired product 3 as white solid.Yield: 78 g, 51%. MS (ESI) m/z 455.37 [M+1]+; 1H NMR (400 MHz, DMSO-d6):δ 4.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55-1.25 (m, 32H), 0.87 (m,6H).

Step-2: Synthesis of 2-hydroxypropane-1,3-diyl didodecanoate (4)

To an ice cold solution of 2-oxopropane-1,3-diyl didodecanoate 3 (75.0g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL)followed by the portion wise addition of sodium cyanoborohydride (12.41g, 0.198 mol). The reaction mixture was stirred at room temperature for16 h. After completion, reaction mixture was diluted with water (400 mL)and extracted with ethyl acetate (3×200 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and solvent was removedunder reduced pressure. The crude was triturated with diethyl ether toafford the desired product 4 as white solid. Yield: 60.0 g, 80%. MS(ESI) m/z 457.48[M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 5.26 (d, J=5.2 Hz,1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H) and0.83 (m, 6H).

Step-3: Synthesis of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid (6)

To an ice-cold solution of 2-hydroxypropane-1,3-diyl didodecanoate 4(10.0 g, 21.91 mmol) in THF (170 mL) was added fumaric acid 5 (2.54 g,21.91 mmol), benzoyl chloride (2.5 mL, 21.91 mmol) and DMAP (0.67 g,5.477 mmol). The resulting mixture was stirred at RT for 16 h. Aftercompletion of reaction (TLC monitoring), reaction mixture wasconcentrated under reduced pressure. The crude was diluted with water(200 mL), adjust pH˜2-3 using 1N-HCl and extracted with 1,2dichloromethane (3×200 mL). The organic layer was separated, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude thus obtained was purified by silica gel (100-200 mesh) columnchromatography eluting with 80% ethyl acetate in hexanes to afford thedesired product 6 as white solid. Yield: 400 mg, 3.30% (un-optimizedyield). LC-MS: m/z 553.64[M−1]; 97.27% purity. 1H NMR (400 MHz,DMSO-d6): δ 13.26 (br s, 1H), 5.17 (d, J=15.8 Hz, 2H), 5.29 (m, 1H),4.30-4.33 (m, 2H), 4.19-4.23 (m, 2H), 2.28 (m, 4H), 1.48 (m, 4H), 1.22(m, 32H) and 0.83 (m, 6H).

Synthesis of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate1-((4-((4-(4-(4-(1-(sec-butyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-yl)phenoxy)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazol-1-ium(8)

To a solution of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid 6(100 mg, 0.18 mmol) in acetonitrile (5 mL) was added4-(4-(4-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one7 (127 mg, 0.18 mmol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 3 h followed by the evaporationof solvent under reduced pressure to get the desired product 8 as whitesolid (M.P. 73.9° C.); yield: 225 mg, quantitative.

Synthesis of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)-1-(4-(1-((2S,3S)-2-hydroxypentan-3-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-ium(10)

To a solution of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid 6(100 mg, 0.18 mmol) in acetonitrile (5 mL) was added4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one9 (126 mg, 0.18 mmol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 3 h followed by the evaporationof solvent under reduced pressure to get the desired product 10 asoff-white solid (M.P. 78.6° C.), yield: 225 mg, quant.

Synthesis of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate4-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-5-fluoropyrimidin-1-ium(12)

To a solution of(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid 6(100 mg, 0.18 mmol) in acetonitrile (5 mL) was added1-(2-((2,4-dichlorobenzyl)oxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imidazole11 (63 mg, 0.18 mmol) at ambient temperature. The resulting reactionmixture was heated up to 50° C. for next 3 h followed by the evaporationof solvent under reduced pressure to get the desired product 12 asoff-white solid (M.P. 71.4° C.), yield: 130 mg, quant.

Anti-Microbial Properties of Fatty Acids:

The antibacterial mode of action of Free Fatty Acids (FFA) is stillpoorly understood, the prime target of FFA action is the cell membrane,where FFAs disrupt the electron transport chain and oxidativephosphorylation; also it can interfere with cellular energy production,generation of peroxidation and auto-oxidation degradation products ordirect lysis of bacterial cells. Medium-chain saturated fatty acids thatlack a kinked structure can be packed more tightly and can reducemembrane fluidity and disrupt electron transport perhaps by restrictingthe movement of carriers within the membrane. The antibacterial effectof long chain unsaturated fatty acids were due to their inhibition offatty acid biosynthesis.

Linoleic acid is GRAS listed long chain fatty acid. Among the long-chainfatty acids, arachidonic acid, linoleic acid, γ-linoleic acid,palmitoleic acid, and palmitic acid had the greatest antimicrobialactivity. Linoleic acid was bactericidal at a concentration of 25 μg/ml;the mean % inhibition was between 80 to 100% for S. mutans; A.actinomycetemcomitans; P. gingivalis; S. gordonii; S. sanguis. Itsactivity against C. albicans was <40%, MIC for linoleic acid against theCandida Species was 0.45 μmoles/ml (which corresponds to 130 ng/ml). Theminimum inhibitory concentration for linoleic acid against Porphyromonasgingivalis was 9 to 78 mcg/ml.

In vitro studies have suggested that gamma linoleic acid (GLA) hassignificant anti-microbial activity against the various oral pathogenicmicroorganisms.

The n-6 fatty acids GLA were bactericidal at a concentration of 25μg/mL. These fatty acid and their esters also showed antimicrobialactivity against the periodontopathogens, A. actinomycetemcomitans, andP. gingivalis, although they were generally most active against the oralstreptococci. GLA and their methyl and ethyl esters were found to haveantimicrobial activities against various oral microorganisms, includingS. mutans, A. actinomycetemcomitans, C. albicans, P. gingivalis, F.nucleatum, and S. gordonii.

EQUIVALENTS

The present disclosure provides among other things compositions andmethods for treating neurological diseases and their complications.While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the systems and methods herein will become apparentto those skilled in the art upon review of this specification. The fullscope of the claimed systems and methods should be determined byreference to the claims, along with their full scope of equivalents, andthe specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted above, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

1. A compound of Formula I:

and pharmaceutically acceptable hydrates, solvates, enantiomers, and stereoisomers thereof; wherein, RH represents selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid; or

wherein, each R₁, R₂ and R₃ independently represents


2. A compound of Formula II:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid; or

wherein, each R₁, R₂ and R³ independently represents


3. A compound of Formula III:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid; or

wherein, each R₁, R₂ and R₃ independently represents


4. A compound of Formula IV:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid; or

wherein, each R₁, R₂ and R₃ independently represents


5. A compound of Formula V:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid or

wherein, each R₁, R₂ and R₃ independently represents


6. A Pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 7. A Pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.
 8. A Pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.
 9. A Pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.
 10. A Pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.
 11. The pharmaceutical composition of claim 6, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 12. The pharmaceutical composition of claim 7, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, topical administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 13. The pharmaceutical composition of claim 8, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, topical administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 14. The pharmaceutical composition of claim 9, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, topical administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 15. The pharmaceutical composition of claim 10, wherein said pharmaceutical composition is formulated with an effective amount of the compound 5 for oral administration, transmucosal administration, topical administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 16. Compounds of claim 1 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 17. Compounds of claim 2 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 18. Compounds of claim 3 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 19. Compounds of claim 4 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 20. Compounds of claim 5 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 21. The A compound of claim 1, wherein the compound has the chemical structure of:


22. The compound of claim 2, wherein the compound has the chemical structure of:


23. The compound of claim 3, wherein the compound has the chemical structure of:


24. The compound of claim 4, wherein the compound has the chemical structure of:


25. The compound of claim 5, wherein the compound has the chemical structure of:


26. A compound of formula VIII:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid or

wherein, each R₁, R₂ and R₃ independently represents


27. A compound of formula IX:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid or

wherein, each R₁, R₂ and R₃ independently represents


28. A compound of formula X:

and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein, RH is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid and arachidonic acid or

wherein, each R₁, R₂ and R₃ independently represents


29. A Pharmaceutical composition comprising the & compound of claim 26 and a pharmaceutically acceptable carrier.
 30. The pharmaceutical composition of claim 29, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 31. A Pharmaceutical composition comprising the compound of claim 27 and a pharmaceutically acceptable carrier.
 32. The pharmaceutical composition of claim 31, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 33. A Pharmaceutical composition comprising the compound of claim 28 and a pharmaceutically acceptable carrier.
 34. The pharmaceutical composition of claim 33, wherein said pharmaceutical composition is formulated with an effective amount of the compound for oral administration, transmucosal administration, parenteral administration, intravenous administration, subdermal administration, rectal administration, buccal administration or transdermal administration.
 35. Compounds of claim 26 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 36. Compounds of claim 27 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 37. Compounds of claim 28 formulated for the treatment of fungal infections, candidiasis and oral infectious diseases.
 38. The compound of claim 26, wherein the compound has the chemical structure of:


39. The compound of claim 27, wherein the compound has the chemical structure of:


40. The compound of claim 28, wherein the compound has the chemical structure of: 